Virus-induced tumors are among the leading causes of cancer-associated morbidity and mortality in humans worldwide with a particularly high prevalence in AIDS patients. Kaposi's sarcoma (KS) is the most common AIDS-associated malignancy and remains highly prevalent despite Highly Active Anti-Retroviral Therapy. KS is caused by the ?-herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV), which is also the etiological agent of two lymphoproliferative B-cell malignancies, the primary effusion lymphoma and the multicentric Castleman's disease. It is well known that the intricate interplay between the innate immune system and viruses dictates the outcome of the viral infection as well as the severity of disease and pathogenesis. Compared with our knowledge of innate immune restriction of acute viral infections, significantly less is known about the cell-intrinsic innate immune mechanisms that control oncogenic viruses including KSHV and related ?-herpesviruses. Over the past few years, it has become evident that the tripartite motif (TRIM) protein family, comprising ~70 members in humans, represents an important class of regulatory molecules in antiviral innate immunity. Despite the wealth of knowledge resulting from recent discoveries in the field of TRIM protein-mediated antiviral defense against RNA viruses, our knowledge about the roles of TRIM proteins in the immune control of DNA tumor viruses and viral oncogenesis is rudimentary. The proposed study is directed towards understanding the functional roles of TRIM proteins in the innate immune control of KSHV and KSHV-induced tumorigenesis. Specifically, our studies aim at identifying novel TRIM proteins that suppress the reactivation or lytic replication of KSHV (Aim 1). Furthermore, we will delineate in precise detail the molecular mechanisms of KSHV restriction for identified TRIM proteins (Aim 2). Finally, we will determine the physiological roles of identified TRIM proteins in controlling the reactivation f the related ?-herpesvirus, Epstein-Barr virus (EBV) (Aim 3). The proposed study will provide important new insights into innate immune defense mechanisms against KSHV and EBV infections, which may provide the foundation for developing novel therapeutic strategies for AIDS-associated malignancies.